Interactions between cells and the extracellular matrix (ECM) regulate fundamental processes of migration, proliferation and differentiation and, thus play critical roles in the development of the vertebrate heart. These interactions are dynamic, reciprocal and appear to be regulated in a temporal and spatial manner. While it is clear that cell-ECM interactions are important in heart development, the underlying functions of the components involved in these interactions remain to be elucidated. The proposed studies will address the hypothesis that there are dynamic interactions between the cellular components of the heart and the ECM which are critical to valvuloseptal morphogenesis. Alterations in the expression, accumulation or organization of molecules involved in these interactions contribute to malformation of the valvuloseptal tissues. The following specific aims will be used to test this hypothesis: 1) to determine the function of specific integrins of the beta1 subfamily in the regulation of adhesion, migration, ECM organization and generation of mechanical tension associated with valvuloseptal development; 2) to investigate the roles of specific ECM components in modulating cellular processes critical to the development of the valvuloseptal tissues; and 3) to determine the role of ECM remodeling by the matrix metalloproteases and the unique A Disintegrin And Metalloprotease (ADAM) proteins in valvuloseptal development. We will use a variety of cell and molecular techniques combined with both in vivo and in vitro assays to determine the functional significance of molecules involved in cell-ECM interactions. These studies will test the functional roles of specific ECM components, their receptors and ECM-modifying proteases in modulating the behavior of cells that contribute to the valvuloseptal tissues including cardiac cushion mesenchymal cells and epicardial-derived cells. These studies will further advance our understanding of the basic cellular mechanisms underlying normal valvuloseptal morphogenesis and how changes in cell-ECM interactions may contribute to congenital heart disease.